The eye is susceptible to bacterial and parasitic infections arising from both traumatic and non-traumatic related events. Infections are a concern after ocular surgery, and precautions are correspondingly taken to prevent the onset of infection. However, even without the invasive trauma of a surgical procedure, infections in the eyelids, conjunctiva, cornea, and other ocular tissues can occur.
Treating infections in ocular tissues can be challenging and/or problematic because of the difficulty in delivering an antibiotic to the affected tissue. In general, ocular infections are treated by local injection, systemic administration, or topical application of an antibiotic. The route of administration depends on the antibiotic selected, the location of the infection, and the type of infection.
The simple and direct approach of topically applying the antibiotic to the exterior of the eye has several benefits, including the avoidance of side effects and the reduced chance of developing resistant strains of bacteria as compared to systemic administration. However, for a variety of reasons, many antibiotics are not amenable or suitable for topical application to the eye.
For example, in order for a topical application to be effective, the antibiotic must be able to penetrate the desired tissue. This may include penetrating the conjunctiva and the cornea. Also, the penetration rate must be sufficient to impart an effective dose. Many drugs do not possess a requisite penetration ability with regard to the tissues of the eye. It should be noted that the external layers of the eye are quite different from the tissues encountered in the stomach and intestinal tract. Thus, while a certain drug may be readily absorbed in the intestines and introduced into the blood supply for systemic administration, the same drug may be incapable of being absorbed by or passing through the substantially avascular outer layers of the conjunctiva or cornea at a minimally acceptable therapeutic concentration. The mechanism of transport or uptake of the drug is entirely different for topical administration than for oral administration.
Another concern is that the antibiotic will be toxic to the eye. A toxic response could include redness, swelling or discharge. Toxicity is especially problematic for topical administration because it is a concentration-dependent phenomenon. The concentration ratio between tear fluid and ocular tissue in topical administration is generally in the range of about 1:500 to 1:1000, due to the penetration gradient. Thus, while a drug may be non-toxic at the minimum effective concentration, the 500% to 1000% increase in concentration associated with topical administration may well induce a toxic response. Again, the fact that oral or systemic administration shows the drug to be compatible with ocular tissue does not predict or address the toxicity issue associated with topical administration.
A further potential unsuitability of an antibiotic is the practicality of topical administration by the patient. Assuming that sufficiently high concentrations of the antibiotic can be used to achieve an effective dose within the target tissue without a toxic response, the application may nonetheless be irritating. An irritation response includes temporary burning, stinging and/or watering of the eye. Beyond whether the increased watering of the eyes washes away so much of the antibiotic composition that an effective dose is prevented, the patient may simply be resistant to complying with the dosage regimen because of the irritation. By failing to comply with the dosing regimen, the treatment efficacy is reduced or eliminated.
Some antibiotics have been found to sufficiently meet the above requirements so as to be applicable to topical administration. Examples of antibiotics that are reported to be useful in ocular topical administration include tobramycin, gentamycin, fluoroquinolone derivatives including norfloxacin, ofloxacin, and ciprofloxacin, naphthyridine, tetracyclines, and erythromycin. These antibiotics are typically administered by applying drops every 2 hours for the first two days and every 4 hours for the next several days. While this may be a common dosing regimen employed with aqueous solutions to treat ocular infections, such an extensive dosing regimen is inconvenient, and obtaining patient compliance can be difficult. Of course, the greater the non-compliance with the regimen, the less effective the treatment. In addition, while some antibiotics may meet other requirements for ophthalmic administration, their use is limited by their poor stability in solution. While these antibiotics can be reconstituted prior to use, reconstitution is limited by the ready availability of sterile pyrogen free solvents, the consistency of the reconstituted dosage, and the conditions under which the reconstituted materials can be stored. Reconstitution of marginally stable antibiotics, which are to be applied in repeated doses, is further limited by the time between the reconstitution and the administration of the final dose. It would be beneficial to provide additional antibiotic formulations that are sufficiently stable so that they do not require reconstitution immediately prior to administration. It would further be beneficial if the antibiotic compositions were adaptable to administration via diverse routes such as parenterally, orally and topically, and if the formulations provided high bioavailability of active antibiotic. It would also be desirable if the formulations were capable of effective topical administration of antibiotics to the eye and treatment of infections of the eye and surrounding tissues. It would be further desirable to provide a topical ophthalmic formulations that are effective against a broad spectrum of bacteria and that can be administered in a less extensive regimen.